Abstract Progress toward developing effective interventions for mental disorders must include the identification of novel intervention targets that are safe, powerful, inexpensive and deployable. Our focus is on one such target? patient memory for the contents of treatment. This target was selected because: (1) patient memory for treatment is poor, (2) poor memory for treatment is associated poorer adherence and poorer outcome, (3) the impact of memory impairment can be minimized by the use of memory support strategies and (4) improved memory for treatment improves outcome. In this proposal we build on an NIMH-funded R34, the results of which provide a preliminary demonstration that the novel target has been engaged and validated. Specifically, we developed and pilot tested an adjunctive intervention?the Memory Support Intervention?to improve patient memory for treatment. The intervention was distilled from the basic, non-patient research in cognitive science and education and is comprised of eight powerful memory promoting strategies that are proactively, strategically, and intensively integrated into treatment-as-usual. The aim of this proposal is to conduct a confirmatory efficacy trial to test whether the Memory Support Intervention improves illness course and functional outcomes. As a `platform' for the next step in investigating this approach, we focus on major depressive disorder (MDD) and cognitive therapy (CT). The rationale is that: (1) MDD is prevalent; (2) there is a need to improve treatment for MDD; (3) CT for MDD is well articulated, there is promising evidence for efficacy, yet there is room for improvement; (4) memory for treatment is poor in MDD; (5) poorer memory in MDD is modifiable and (6) promising data from the R34 suggests that adding memory support to CT improves outcome, with a specific indication of longer-term benefit among individuals with less than 16 years of education. Over a four-year period, adults with MDD (n = 178, including 20% for potential attrition) will be randomly allocated to CT+Memory Support or CT-as-usual and they will be assessed at baseline, post- treatment, and at 6 and 12 months follow-up. We will compare the effects of CT+Memory Support vs. CT-as- usual to determine if the new intervention improves the course of illness and reduces functional impairment (Aim 1). We will determine if patient memory for treatment (the target) mediates the relationship between treatment condition and outcome (Aim 2). We will evaluate if previously reported poor treatment response subgroups moderate target engagement (Aim 3). This research has the potential to enhance outcomes across a broad range of interventions. Consultants with expertise in community-based treatment and doctor-patient communication will assist the team to begin to develop the broader applications. This research will contribute knowledge to RDoC as a cross-diagnostic construct related to the Cognitive Systems RDoC domain?poor memory for treatment?is the intervention target. Also, declarative memory and working memory, which are constructs within the Cognitive Systems RDoC domain, will be measured.